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Given the progressive deteriorating nature of this illness, managing patient
and caregiver expectations about treatment is crucial. Most ChEI studies
have been conducted for 3 to 6 months in patients with mild to moderate
disease (10 to 26 out of 30 on the Mini-Mental State Examination [MMSE]
[29]). These studies have generally utilized the Alzheimer’s Disease Assessment
Scale (ADAS-cog) (30) as a primary cognitive outcome measure, as well as
a structured clinical global impression measurement. The ADAS-cog is a
70-item scale that tests various cognitive domains and is more sensitive
to change than is the MMSE. AD patients with moderate disease tend to worsen
by 7 to 8 points on the ADAS-cog yearly (31). A change of 4 or more points
(that is, representing 6 months of cognitive life for an AD patient) has
arbitrarily been chosen as a measure of significant improvement in many
of these trials. The pivotal ChEI studies consistently showed that average
ADAS-cog scores at the end of the studies were statistically better in
drug-treated patients, compared with placebo, whereas the number of patients
who experienced significant benefit as defined above was modest, about
30% for drug-treated patients, compared with 18% of placebo-treated patients
(unpublished research). Results of the clinical global impression ratings
for patients demonstrating minimal, moderate, and marked improvement on
ChEIs, compared with placebo were similar. Because most clinicians will
be unable to perform an ADAS-cog in their office, measuring cognitive improvement—especially
over a period of less than 1 year—can be challenging. However, obtaining
a history from caregivers that suggests a decrease in apathy and improved
function and communication abilities will often suffice as markers of ChEI
response. Most provincial drug formularies reimburse patients for the use
of ChEIs when prescribed for AD patients with documented MMSE scores of
10 to 26. On average, the MMSE declines by only 3 points yearly (32); for
this reason, as an outcome measure for clinicians, the instrument should
be used for longer-term use only (1 year). Despite what appears to be modest
efficacy, increasing evidence exists that these drugs have significant
effects on functional abilities, behaviour, caregiver burden, and quality
of life (33). In addition, studies suggest that clinicians can achieve
significant cost savings, despite the significant initial costs of these
drugs (34,35). Finally, there is some evidence that these drugs have disease-modifying
effects and have benefits beyond cholinesterase inhibition (36). For example,
a recent study documented effects on amyloid precursor protein metabolism,
suggesting a possible effect on amyloid plaque deposition (37).
With the availability of 3 ChEIs, clinicians are faced with deciding which
drug to choose. Although no published head-to-head studies exist, examination
of individual published efficacy and side-effect rates appear to overlap
significantly (unpublished research). They are all safe with respect to
potential drug interactions. Donepezil and galantamine are metabolized
by CYP 2D6 and 3A4, though extensive drug-interaction testing suggests
few clinically important interactions (38–42). Rivastigmine undergoes hydrolysis,
making it less likely for involvement in significant drug interactions
(43). Because these drugs are marketed at similar prices, economic considerations
are insignificant, but from a practical administration perspective, they
differ. Donepezil is a once-daily medication, which is initiated at 5 mg
and increased to 10 mg after 1 month (1-dose titration step) (44). Galantamine
is administrated twice daily, starting at 4 mg twice daily, with an increase
to 8 mg twice daily after 1 month. The manufacturer recommends that the
dosage be increased to 12 mg twice daily after a further month (2-dose
titration steps); this “might provide additional benefit for some patients”
(44). In fact, most of the pivotal galantamine studies used dosages of
24 to 32 mg daily (24–28). Rivastigmine is administered twice daily, beginning
with 1.5 mg twice daily, with dosage increases to 3 mg twice daily, 4.5
mg twice daily, and 6 mg twice daily (3-dose titration steps) after a minimum
of 2 weeks between dosage changes and dependent on tolerability (44). Should
differences in ease of administration guide clinician choice of ChEI? Not
necessarily. These 3 drugs have distinct pharmacologic profiles. Donepezil
is a piperidine that is highly specific for acetylcholinesterase with high
central, compared with peripheral, cholinomimetic activity. Rivastigmine
is a carbamate that is a pseudo-irreversible inhibitor of cholinesterases.
Unlike donepezil, it inhibits both acetylcholinesterase and butyrylcholinesterase.
The latter becomes increasingly prevalent as AD progresses and may play
a role in AD symptomatology, especially in late stages of the illness.
Galantamine is a competitive reversible inhibitor of acetylcholinesterase,
and it allosterically modulates nicotinic receptors, enhancing cholinergic
activity. While the clinical significance of these pharmacologic differences
awaits head-to-head trials, they do suggest that lack of effectiveness
or poor tolerability of 1 agent may not occur with the other 2. This situation
would be analogous to using a second (or third) selective serotonin reuptake
inhibitor (SSRI) to treat a depression patient who has not responded to
the first, given their distinct chemical structures and binding specificities.
Preliminary data supporting the practice of switching suggest that, indeed,
a second ChEI may be better tolerated and more effective, regardless of
the switched-to-or-from agent (45).
It has also become increasingly clear that the indications for ChEI can
be extended beyond AD patients who score 10 to 26 on the MMSE. In a study
of patients with moderate-to-severe AD (MMSE scores 5 to 17 out of 30),
63% of donepezil-treated patients were rated as improved or unchanged at
6 months, compared with 42% of placebo-treated patients (20). The investigators
argue that these results are even better than are studies treating mild-to-moderate
disease. This study, combined with data that demonstrate neuropathological
cholinergic markers do not fall appreciably until later stages of AD, provides
support for the use of ChEIs in moderate and severe AD (46). In an RCT
with rivastigmine, 120 patients with dementia with Lewy bodies (DLB) improved
significantly on measures of behaviour and cognition, compared with placebo-treated
patients (47). Similarly, other open-label studies suggest positive responses
in DLB patients who are treated with donepezil and rivastigmine (48,49).
In a recently published study, 592 patients with vascular dementia (VaD)
or AD and cerebrovascular disease were randomized to 6 months of treatment
with either galantamine or placebo (50). Patients treated with galantamine
had significantly better cognitive function, compared with placebo, with
results appearing strikingly similar to the ChEI studies in AD. Although
these data provide strong argument with respect to expanding the indications
for ChEI for moderate-to-severe AD, DLB, and VaD, some caution is necessary
before deeming these drugs to be innocuous cure-alls. ChEIs are unhelpful
in patients with frontotemporal dementia who generally have no significant
cholinergic deficits, and in fact, ChEI treatment may worsen some patients’
dementia (51). For example, in a small RCT in patients with progressive
supranuclear palsy, no change occurred in the primary outcome measures
of cognition and behaviour, but patients showed significant worsening in
ADL mobility measures (52). Studies currently under way are examining the
use of ChEIs in mild AD and MCI (mild cognitive impairment), Down syndrome,
Parkinson’s disease, and delirium.
Hormone Replacement Therapies
The use of hormone replacement therapy (HRT) to treat AD is based on epidemiological,
clinical, and neuropathological observations. It is generally accepted
that women have a higher prevalence of AD, compared with men (53). Women
are estrogen-deficient after menopause, whereas men continue to benefit
from estrogen coverage throughout life as circulating testosterone undergoes
aromatization to estradiol. Significant data reveal that postmenopausal
women treated with HRT have improved cognitive function (54), and a large
number of epidemiological studies suggest that women who have undergone
HRT are subsequently at lower risk for developing AD (53). Biological mechanisms
proposed for these effects have included estrogen’s antioxidant and antiinflammatory
properties, interactions with neurotransmitter systems such as acetylcholine,
neurotrophic effects (including direct effects on basal forebrain cholinergic
neurons), alterations of apolipoprotein E and beta-amyloid levels via stimulation
of secretase metabolism, and increased cerebral blood flow and glucose
utilization (55,56). Unfortunately, despite the enthusiasm for this biologically
plausible treatment, several large, well-designed, placebo-controlled RCTs
of estrogen replacement in women with AD were negative (57,58). A potential
criticism of these studies is that using HRT in women who already have
the disease is akin to “shutting the barn door after the horses have bolted,”
and the use of HRT should be directed at postmenopausal women who do not
have the disease to prevent or delay onset of the illness (59). Although
such studies are underway in Canada and the US, a large RCT published recently
has once again dampened enthusiasm. In this study, 7705 postmenopausal
women were randomized to receive placebo or raloxifene, a selective estrogen
receptor modulator (60). After 3 years, raloxifene did not demonstrate
any effects on improving cognition or on slowing cognitive decline, compared
with placebo. Further studies still need to address issues, such as the
type of HRT used (for example, conjugated estrogens vs 17 beta-estradiol
(61) or estrogen alone vs estrogen plus progesterone), timing of HRT, whether
HRT may have augmenting properties when combined with ChEIs (62), or whether
there is a role for HRT in men (63). At the moment, however, insufficient
evidence-based data exist for clinicians to recommend HRT use for AD patients.
Antiinflammatory Therapies
Similar to the experience with HRT, antiinflammatory therapy for AD is
a biologically plausible treatment that has yet to be proven clinically
valuable in RCTs. It has long been known that markers of inflammation are
present in the neuropathology of AD, including reactive microglia surrounding
plaques, activated complement, and the presence of numerous acute phase
markers (64). Supported by several epidemiological studies suggesting that
patients exposed to nonsteroidal antiinflammatory drugs (NSAIDs) have a
lowered risk of developing AD (65), investigators have studied a number
of different antiinflammatories in RCTs. A small, early pilot study with
indomethicin appeared positive (66), whereas more recent studies with diclofenac
(67), prednisone (68), and hydroxychloroquine (69) were all negative. A
recent epidemiological study, however, provides a possible explanation
for the failure of these RCTs. The Rotterdam study followed 7000 subjects
without dementia age 55 years and over for up to 8 years (70). Based on
a review of pharmacy records, that study determined that the relative risk
of developing AD was dramatically reduced by NSAID use, but only in subjects
who used these drugs for 2 or more years. It also appeared that most of
this protective effect occurred prior to 2 years, before dementia was diagnosed.
These results suggest that NSAID therapy for AD may require prolonged use
for periods well before clinical symptoms are evident. Notably, NSAIDs,
steroids, and hydroxychloroquine have overlapping but different pharmacologic
properties, making it unclear which of these might provide clinical benefit.
Several studies are under way with cycloxygenase 1 and cycloxygenase 2
inhibitors in AD and MCI patients, which will help clarify their role.
Presently, however, there are insufficient evidence-based data to recommend
antiinflammatory use for the treatment of AD.
Antioxidant Therapies
Neuropathological data suggest that oxidative stress and the accumulation
of free radicals lead to neuronal damage in AD (71). Therefore, several
studies have attempted to use compounds with antioxidant effects to treat
AD. In the largest study to date, 341 AD patients were randomized to treatment
with the antioxidants vitamin E, selegiline, and the combination or placebo
(72). Unfortunately, the study suffered from a failed randomization that
resulted in no significant differences in the unadjusted analysis. With
statistical adjustment for differences in baseline cognition, vitamin E
and selegiline appeared to delay progression of AD by 7 to 8 months over
a period of 2 years. Aside from the methodological issue described, other
concerns raise the question of result validity; specifically, the choice
of outcome measures, the lack of demonstrable effect on cognition, and
the use of high dosages of vitamin E (2000 IU daily). With the recent failure
of vitamin E to demonstrate cardioprotective and anticancer effects (73),
clinicians may be less likely to recommend vitamin E, even with its well-established
safety. Research continues on the use of antioxidant vitamins, and a large
US study is attempting to clarify the role of vitamin E in the treatment
or prevention of AD. Other compounds with more powerful antioxidant effects
are also being studied. For example, a small RCT with N-acetyl cysteine,
which has a broader range of activity to neutralize reactive intermediates,
suggested that it was well tolerated with possible effects on cognition
and ADL (74).
Treatment of Vascular Risk Factors
Treatment of vascular risk factors may become a crucial component of AD
pharmacotherapy. That patients can suffer from mixed AD and VaD has long
been recognized, but the contribution to “pure” AD of smaller vascular
lesions has been appreciated only recently. In “The Nun Study,” investigators
studied patients with neuropathologically diagnosed AD and determined that
patients with any infarcts—and especially lacunar infarcts in the basal
ganglia, thalamus, or deep white matter—were more cognitively impaired
and more likely to meet clinical criteria for dementia (75). Epidemiological
studies suggest that patients with hypertension are more likely to develop
cognitive impairment, but treatment with antihypertensives lowered the
risk (76). Most persuasively, in a large RCT, 2418 subjects with hypertension,
but no dementia, were randomized to antihypertensive therapy with nitrendipine,
a calcium channel blocker, or placebo and followed for an average of 2
years (77). Results indicated that treatment with a calcium channel blocker,
reduced the incidence of dementia by 50%. Surprisingly, most reduction
was due to a decrease in the number of patients diagnosed with AD. In a
large epidemiological study, older subjects who were prescribed statins
for hypercholesterolemia had a substantially lower risk of developing dementia
(78). Finally, it is well documented that elevations in serum levels of
homocysteine are a risk factor for cardiovascular disease and stroke. Recent
data from the Framingham study concluded that increased plasma homocysteine
is a strong independent risk factor for developing dementia (79). The authors
suggest that vitamin therapy and dietary supplementation with folic acid,
Vitamin B6, and B12 could reduce plasma homocysteine levels and possibly
decrease the risk of developing dementia.
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